The four main components of the RREPs were significantly less frequent in children with stable chronic lung and airway diseases or with a ventilatory defect of neuromuscular origin than in age-matched healthy controls. This suggests that chronic ventilatory defects in children can be associated with an impaired cortical processing of afferent respiratory signals. In addition, the RREPs abnormalities were more pronounced in asthmatic children and in children with CF than in children with a ventilatory defect due to a neuromuscular disease. Indeed, the N1 and P2 components were significantly less frequently seen in the patients with asthma or CF, and the number of patients exhibiting no RREPs at all was significantly greater in the CF group.
Physiological considerations
The CF patients enrolled in this study were comparable to those evaluated in previous studies [
20,
21]. The respiratory mechanics of these patients is characterized by an increase in the work of breathing as assessed by the high values of inspiratory and diaphragmatic pressure time products. This elevated work of breathing is the signature of a chronically augmented mechanical load, with an elastic component attested by the presence of dynamic hyperinflation and a resistive component in line with the chronic, irreversible, airflow obstruction. Breathing against an elevated background resistance increases the threshold for detection of an added resistance [
22]. Yet it has been shown that this also reduces the amplitude of the RREPs elicited by the sudden application of a resistive load [
6]. In fact, RREPs elicited by an additional resistance are present only if this resistance exceeds the value of the detection threshold [
6]. The increase in background load could thus explain why the RREPs were more abnormal in the CF patients than in the other patient groups. However, we did not study resistance-elicited RREPs, but rather occlusion-induced ones. By definition, and except if the capacity to detect a resistance is totally abolished, the infinite resistance that corresponds to an inspiratory occlusion should be above the detection threshold and thus still elicit a RREP even in the presence of an increased background resistance [
6]. This has however not been studied specifically, and how a very high load sustained indefinitely as in our CF patients can modify the RREP threshold as compared to a resistance detection threshold is not known. Of note, and even though no statistically significant trend was detected, some of the CF patients who completely missed the RREPs were among the patients with the most severe respiratory mechanics and respiratory muscle abnormalities (data not shown). That the RREPs abnormalities observed were dichotomous (absence of components, but normal latencies and amplitudes of the preserved components) seems to support the role of the background load. We however acknowledge that this hypothesis would be have been much strengthened if we had demonstrated that our CF patients were less apt than the other patients to detect added inspiratory loads. We did not assess this point, and to our knowledge, there is currently insufficient data to support this hypothesis.
Patients with neuromuscular weakness but without overt respiratory mechanics abnormalities do not breathe against increased loads. This is also the case for asthmatic patients with reversible airway obstruction when they are in clinical remission, which was the case for all the asthmatic patients in the present study. Nevertheless we observed RREPs abnormalities in these two categories of patients. The "increased background resistance" mechanism is therefore probably not the unique one to call upon to explain our findings.
Technical explanations, such as differences in skin impedance between control subjects and sick patients in general, and between CF patients and others in particular, can be ruled out because we paid careful attention to check and maintain the impedance of our recording montage as low as possible in all cases. From a technical point of view, a greater incidence of the N1 peak than the P1 peak may be surprising for a pattern of neural activity that has been reported previously to occur as a linked sequence of neural events. This may be the result of our exclusive use of the C
z reference electrode montage. Indeed, the P1 peak dipole is best modelled in the somatosensory cortex recorded with electrodes placed 2 cm caudal to the C
3 and C
4 sites [
23]. The N1 peak is best modelled at the C
z site using a non-cephalic reference. Our montage was nevertheless able to identify normal RREPs with the full sequence of components in healthy subjects.
It must also be noted that we did not perform the respiratory mechanics and respiratory muscles measurements in the patients with asthma or a neuromuscular disease. The absence of abnormalities in these patients is therefore only assumed, and we may thus have missed an increase in inspiratory load in some of the participants. Beside this possibility, patients with weak inspiratory muscles faced to an inspiratory occlusion develop an inspiratory effort that is closer to their maximal inspiratory output than patients exhibiting normal muscle strength. It cannot be excluded that this interferes in some way with the production of the RREPs.
The role of inflammation must also be discussed. Patients with asthma and CF characteristically exhibit airway inflammation in the broadest sense of the term, although the pathophysiology and the course of the inflammatory process differ between the two diseases. In CF, airway inflammation occurs early in life, is poorly controlled by anti-inflammatory drugs, and is closely linked to bacterial airway infection [
24]. In asthma, inflammation can occur at different ages, can be efficaciously controlled by inhaled corticosteroids, and is not linked to bacterial airway infection [
25]. As a result, asthma and CF have radically different clinical and functional profiles. Schematically, asthma can be viewed as a chronic disease featuring episodes of reversible airway obstruction of various magnitudes. CF is a chronic lung disease characterised by a chronic and progressively worsening airway obstruction. Hyperinflation is early and constant in CF [
20,
26], but it is observed only in the most severe asthmatic patients experiencing poor therapeutic control [
27]. Our observation of greater RREPs abnormalities in CF and asthma children than in children with neuromuscular disease may suggest that chronic respiratory inflammation may interfere with the processing of respiratory afferent information by the brain, whatever the underlying mechanism. Indeed the number of CF patients exhibiting no RREP at all was significantly higher than in any of the other patient groups studied. Of note, data in the literature indicate that there may be a relationship between the brain and airway inflammation [
28]. Indeed, it has been shown in patients with allergic asthma that some brain regions may be hyperresponsive to disease specific emotional and afferent physiological signals, which may contribute to the dysregulation of peripheral processes, such as airway inflammation [
28].
Clinical perspectives
Our results are not out of line with the observations made in asthmatic children by Davenport
et al. [
14]. These researchers observed that the P1 peak was absent in 6 of 11 patients with life-threatening asthma, whereas it was present in 14 of the 15 control asthmatic patients and in all the 14 nonasthmatic patients. Some of the asthmatic patients included in our study had a history of near-fatal asthma (n = 7), and among them 43% and 57% lacked the P1 component on the right and the left side, respectively, which fits with the 54% proportion reported by Davenport
et al. [
14]. In our study, the presence of RREPs abnormalities in the asthmatic children having no history of near-fatal asthma does not agree with the results of Davenport
et al. [
14], but this may be explained by different population characteristics. To the best of our knowledge, our study is the first to provide RREPs data in children with CF and with a restrictive ventilatory defect of neuromuscular origin.
Davenport
et al. [
14] interpreted their findings within the frame of the blunted perception of inspiratory load that has been observed in asthmatic patients with a history of life-threatening asthma, be they adults [
12] or children [
11] for load detection [
13] or for load magnitude estimation. Subjacent to this interpretation is the temptation to use the RREPs as a possible prognostic tool, for example to identify patients at risk of sudden, unexpected acute exacerbations of their disease without recognising them. Clearly the gap to bridge before this can become a reality is very wide at present. Specifically designed clinical studies are needed. Our data however open the possibility that this concept could apply not only to asthma, but also to other chronic inflammatory respiratory disorders in children. The first step to take in the direction of a clinical use of the RREPs would be, as discussed above, seems to put this neurophysiological information in the perspective of a description of the load detection and load magnitude estimation performances in patients with CF and neuromuscular disease. Then putative correlates with clinical profiles could be sought.